Host and microbial basis of human ulcerative colitis and pouchitis: Identification, role, mechanisms, and resource development of host susceptibility and pathobiont factors

项目概要/摘要 炎症性肠病（IBD）是由宿主、环境和微生物因素共同作用的结果， 每一种都是必要的，但不足以引起疾病。然而，在知识方面仍然存在重大差距，其中， 什么是疾病易感性的基础并加速IBD的发作。需要更好地了解 导致这些疾病的原因仍然是一个挑战。疾病发作后，许多混杂因素和 复杂的情况使得要解开无数的促成因素成为问题。毫不奇怪，大多数人 主题研究未能超越描述和联想。无法理清因果关系， 时间基础进一步阻碍了改善临床管理和结果以及开发有效的 风险分层和疾病预防战略。为了解决这个问题，我们提出了一个多学科的 团队方法，将使用独特的临床模型的透镜，以获得变革性的见解， 在IBD中移动针头。该模型涉及一组难治性溃疡性结肠炎患者 (UC)接受过全直肠结肠切除回肠袋肛门吻合术（UC-IPAA）， 在疾病发展前后进行跟踪，并作为自己的对照。这些患者中有一半将 在两年内发展出回肠袋的炎症状况（结肠袋炎）。在最初的探索性研究中， 在这些患者中，有两个发现导致了以下假设：[1] IBD患者表现出 一种对微生物来源的信号的异常转录反应，使它们容易受到 结肠袋炎的发展，但不足以引起疾病。[2]特异性粘膜致病菌 通过选择或获得毒力因子而出现， 遗传易感性的背景。关于后者，具体脆弱拟杆菌的差异 在管腔和粘膜菌株中的荚膜多糖（CPS）生物合成基因簇可能会转化一种 微生物转化为病原体。本研究的目的有三：（1）探讨刺激因素、作用和 可能促进疾病的异常UC袋转录组的特定宿主基因的功能影响 易感性，通过采用单细胞方法来定义细胞类型和特异性贡献， （2）鉴定和分离参与促进结肠袋炎的微生物，包括CPS变体， 确定它们对宿主上皮细胞和免疫细胞的功能影响以及对启动的作用和贡献 （3）为更广泛的社区开发研究资源，以促进基于发现或 提出假设的科学这项研究将由一个多学科专家小组进行， 合作和协同增效的成功记录。该提案将基础、翻译和临床联系起来 科学研究的重点是宿主和微生物细胞的分子和遗传机制， 目标是为未来多种类型的复杂免疫疾病的干预措施奠定基础;最终，我们 将能够改变这些患者的预后。

PROJECT SUMMARY/ABSTRACT Inflammatory bowel diseases (IBD) result from the convergence of host, environmental, and microbial factors, each necessary, but not sufficient to cause disease. Yet, significant gaps in knowledge remain – among them, what underlies disease susceptibility and precipitates the onset of IBD. The need to better understand the causes that lead to these diseases remains a challenge. Post disease onset, numerous confounders and complications make it problematic to unravel the myriad of contributing factors. Not surprisingly, most human subject studies fail to go beyond description and association. Inability to sort out cause-effect relationship on a temporal basis further hinders efforts to improve clinical management and outcomes and to develop effective strategies for risk stratification and disease prevention. To address this issue, we propose a multi-disciplinary team approach that will use the lens of a unique clinical model to gain transformative insights that will help move the needle in IBD. The model involves a subset of patients with medically-refractory ulcerative colitis (UC) who have undergone total proctocolectomy with ileal pouch anal anastomosis (UC-IPAA) and who can be followed before and after disease development and serve as their own controls. Half of these patients will develop an inflammatory condition of their ileal pouch within two years (pouchitis). In an initial exploratory study of these patients, two discoveries were made which led to the following hypotheses: [1] IBD patients exhibit an anomalous transcriptional response to microbiota-derived signals that renders them susceptible to the development of pouchitis, but is not sufficient to cause disease. [2] Specific mucosal pathobionts that emerge through selection or acquisition of virulence factors trigger pouchitis on the patient's background of genetic susceptibility. With regard to the latter, differences in specific Bacteroides fragilis capsular polysaccharide (CPS) biosynthetic gene clusters among luminal and mucosal strains may transform a commensal microbe to a pathobiont. Three aims are proposed: (1) to investigate the stimuli, role, and functional impact of specific host genes of the anomalous UC pouch transcriptome that may promote disease susceptibility, by employing single-cell approaches to define cell-type and -specific contributions and mechanisms; (2) to identify and isolate microbes involved in promoting pouchitis including CPS variants and determine the their functional impact on host epithelia and immune cells and role and contribution to initiation of disease, (3) to develop a research resource for the broader community to advance discovery-based or hypothesis-generating science. The study will be conducted by a multi-disciplinary team of experts with a proven and successful record of collaboration and synergy. The proposal links basic, translational, and clinical scientific research by focusing on molecular and genetic mechanisms of host and microbial cells with the objective of building a base for future interventions for many types of complex immune diseases; ultimately, we will be able to alter the outcome for these patients.